Novel aza-bicyclic compounds and their use as stimulators of soluble guanylate cyclase

ABSTRACT

The present application relates to novel azabicyclic compounds, processes for their preparation, their use alone or in combinations for the treatment and/or prevention of diseases, and their use for producing medicaments for the treatment and/or prevention of diseases, especially for the treatment and/or prevention of cardiovascular disorders.

The present application relates to novel azabicyclic compounds,processes for their preparation, their use alone or in combinations forthe treatment and/or prevention of diseases, and their use for producingmedicaments for the treatment and/or prevention of diseases, especiallyfor the treatment and/or prevention of cardiovascular disorders.

One of the most important cellular transmission systems in mammaliancells is cyclic guanosine monophosphate (cGMP). Together with nitricoxide (NO), which is released from the endothelium and transmitshormonal and mechanical signals, it forms the NO/cGMP system. Guanylatecyclases catalyze the biosynthesis of cGMP from guanosine triphosphate(GTP). The representatives of this family disclosed to date can bedivided both according to structural features and according to the typeof ligands into two groups: the particulate guanylate cyclases which canbe stimulated by natriuretic peptides, and the soluble guanylatecyclases which can be stimulated by NO. The soluble guanylate cyclasesconsist of two subunits and very probably contain one heme perheterodimer, which is part of the regulatory site. The latter is ofcentral importance for the mechanism of activation. NO is able to bindto the iron atom of heme and thus markedly increase the activity of theenzyme. Heme-free preparations cannot, by contrast, be stimulated by NO.Carbon monoxide (CO) is also able to attach to the central iron atom ofheme, but the stimulation by CO is distinctly less than that by NO.

Through the production of cGMP and the regulation, resulting therefrom,of phosphodiesterases, ion channels and protein kinases, guanylatecyclase plays a crucial part in various physiological processes, inparticular in the relaxation and proliferation of smooth muscle cells,in platelet aggregation and adhesion and in neuronal signaltransmission, and in disorders caused by an impairment of theaforementioned processes. Under pathophysiological conditions, theNO/cGMP system may be suppressed, which may lead for example to highblood pressure, platelet activation, increased cellular proliferation,endothelial dysfunction, atherosclerosis, angina pectoris, heartfailure, myocardial infarction, thromboses, stroke and sexualdysfunction.

A possible way of treating such disorders which is independent of NO andaims at influencing the cGMP signaling pathway in organisms is apromising approach because of the high efficiency and few side effectswhich are to be expected.

Compounds, such as organic nitrates, whose effect is based on NO have todate been exclusively used for the therapeutic stimulation of solubleguanylate cyclase. NO is produced by bioconversion and activates solubleguanylate cyclase by attaching to the central iron atom of heme. Besidesthe side effects, the development of tolerance is one of the crucialdisadvantages of this mode of treatment.

Some substances which directly stimulate soluble guanylate cyclase, i.e.without previous release of NO, have been described in recent years,such as, for example, 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole[YC-1, Wu et al., Blood 84 (1994), 4226; Mülsch et al., Brit. J.Pharmacol. 120 (1997), 681], fatty acids [Goldberg et al., J. Biol.Chem. 252 (1977), 1279], diphenyliodonium hexafluorophosphate [Pettiboneet al., Eur. J. Pharmacol. 116 (1985), 307], isoliquiritigenin [Yu etal., Brit. J. Pharmacol. 114 (1995), 1587] and various substitutedpyrazole derivatives (WO 98/16223).

Fused pyrazole derivatives are described inter alia in WO 98/16507, WO98/23619, WO 00/06567, WO 00/06569, WO 02/42299, WO 02/42300, WO02/42301, WO 02/42302, WO 02/092596, WO 03/004503 and WO 03/095451 asstimulators of soluble guanylate cyclase. However, it has emerged thatthese compounds sometimes display disadvantages in terms of theirphysicochemical properties such as, for example, their solubility, or inrelation to their in vivo properties, such as, for example, theirbehavior in the liver, their pharmacokinetic behavior, their dose-effectrelation and/or their metabolic pathway.

In addition, WO 2005/030121 claims fused azoles for the treatment ofneoplastic diseases.

It was an object of the present invention to provide novel substanceswhich act as stimulators of soluble guanylate cyclase and display animproved therapeutic profile by comparison with compounds known in theprior art.

The present invention relates to compounds of the general formula (I)

L-CH₂-M-Q   (I),

in which

-   -   L is phenyl, pyridyl, furyl, thienyl, thiazolyl, oxazolyl,        isothiazolyl or isoxazolyl, each of which may be substituted up        to twice, identically or differently, by halogen, cyano,        (C₁-C₄)-alkyl, trifluoromethyl and/or (C₂-C₄)-alkynyl,        -   or        -   is (C₅-C₇)-cycloalkyl which may be substituted up to twice,            identically or differently, by fluorine and/or            (C₁-C₄)-alkyl,    -   M is a bicyclic heteroaryl group having one of the formulae (a)        to (i)

-   -   -   in which        -   * is the point of linkage to the —CH₂-L group,        -   ** is the point of linkage to the Q group,        -   A, B and D are each CH, CR^(‘)or N, with a maximum of two of            the ring members A, B and D simultaneously being N and in            which        -   R¹ is a substituent selected from the series halogen, cyano,            (C₁-C₄)-alkyl, trifluoro-methyl, amino, (C₁-C₄)-alkoxy and            trifluoromethoxy,            -   where, in the event that the substituent R¹ occurs more                than once, its meanings may be identical or different,

and

-   -   E is O or S,

and

-   -   Q is an unsaturated or aromatic 5- or 6-membered heterocycle        having up to four heteroatoms from the series N, O and/or S,        which may be substituted up to four times, identically or        differently, by radicals selected from the group consisting of        halogen, azido, nitro, cyano, oxo, thioxo, —R², —C(═O)—R²,        —C(═O)—OR², —C(═O)—NR²R³, —O—(C═O)_(n)—R², —O—C(═O)—OR²,        —O—C(═O)—NR²R³, —S(O)_(p)—R², —SO₂—OR², —SO₂—NR²R³,        —NR²—(C═O)_(n)—R³, —NR²—SO₂—R³, —NR²—C(═O)—OR³, —NR⁴—C(═O)—NR²R³        and —NR⁴—SO₂—NR²R³, in which        -   n is the number 0 or 1,        -   p is the number 0, 1 or 2,        -   R², R³ and R⁴ are identical or different and are            independently of one another hydrogen, (C₁-C₆)-alkyl,            (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkenyl,            (C₆-C₁₀)-aryl, 4- to 8-membered heterocyclyl or 5- to            10-membered heteroaryl,        -   and/or        -   R² and R³ or R² and R⁴ together with the radical to which            they are both respectively bonded may form a 4- to            8-membered heterocycle,            -   where R², R³ and R⁴ in turn may optionally be                substituted up to five times, identically or                differently, by radicals selected from the group                consisting of halogen, azido, nitro, cyano,                (C₁-C₆)-alkyl, trifluoromethyl, (C₁-C₆)-acyl,                hydroxycarbonyl, (C₁-C₆)-alkoxycarbonyl, aminocarbonyl,                mono- and di-(C₁-C₆)-alkylaminocarbonyl, hydroxy,                (C₁-C₆)-alkoxy, trifluoromethoxy, (C₁-C₆)-acyloxy, oxo,                mercapto, (C₁-C₆)-alkylthio, amino, mono- and                di-(C₁-C₆)-alkylamino, (C₁-C₆)-acylamino,                (C₁-C₆)-alkoxycarbonylamino, (C₃-C₈)-cycloalkyl,                (C₃-C₈)-cycloalkenyl and 4- to 8-membered heterocyclyl,

and the N-oxides, salts, solvates, salts of the N-oxides and solvates ofthe N-oxides and salts thereof.

Compounds according to the invention are the compounds of the formula(I) and the salts, solvates and solvates of the salts thereof, thecompounds which are encompassed by formula (I) and are of the formulaementioned hereinafter, and the salts, solvates and solvates of the saltsthereof, and the compounds which are encompassed by formula (I) and arementioned hereinafter as exemplary embodiments, and the salts, solvatesand solvates of the salts thereof, insofar as the compounds encompassedby formula (I) and mentioned hereinafter are not already salts, solvatesand solvates of the salts.

Compounds according to the invention are likewise N-oxides of thecompounds of the formula (I), and the salts, solvates and solvates ofthe salts thereof.

The compounds according to the invention may, depending on theirstructure, exist in stereoisomeric forms (enantiomers, diastereomers).The present invention therefore relates to the enantiomers ordiastereomers and respective mixtures thereof. The stereoisomericallypure constituents can be isolated in a known manner from such mixturesof enantiomers and/or diastereomers.

Where the compounds according to the invention can occur in tautomericforms, the present invention encompasses all tautomeric forms.

Salts preferred for the purposes of the present invention arephysiologically acceptable salts of the compounds according to theinvention. However, salts which are themselves unsuitable forpharmaceutical applications but can be used for example for isolating orpurifying the compounds according to the invention are also encompassed.

Physiologically acceptable salts of the compounds according to theinvention include acid addition salts of mineral acids, carboxylic acidsand sulfonic acids, e.g. salts of hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonicacid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonicacid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid,tartaric acid, malic acid, citric acid, fumaric acid, maleic acid andbenzoic acid.

Physiologically acceptable salts of the compounds according to theinvention also include salts of conventional bases such as, for exampleand preferably, alkali metal salts (e.g. sodium and potassium salts),alkaline earth metal salts (e.g. calcium and magnesium salts) andammonium salts derived from ammonia or organic amines having 1 to 16 Catoms, such as, for example and preferably, ethylamine, diethylamine,triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine,dibenzylamine, N-methyl-morpholine, arginine, lysine, ethylenediamineand N-methylpiperidine.

Solvates refer for the purposes of the invention to those forms of thecompounds according to the invention which form a complex in the solidor liquid state through coordination with solvent molecules. Hydratesare a specific form of solvates in which the coordination takes placewith water. Solvates preferred in the context of the present inventionare hydrates.

The present invention also encompasses prodrugs of the compoundsaccording to the invention. The term “prodrugs” encompasses compoundswhich themselves may be biologically active or inactive but areconverted during their residence time in the body into compoundsaccording to the invention (for example by metabolism or hydrolysis).

In the context of the present invention, the substituents have thefollowing meaning unless otherwise specified:

(C₁-C₆)-Alkyl and (C₁-C₄)-alkyl are in the context of the invention astraight-chain or branched alkyl radical having respectively 1 to 6 and1 to 4 carbon atoms. A straight-chain or branched alkyl radical having 1to 4 carbon atoms is preferred. Examples which may be preferablymentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl,sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl and n-hexyl.

(C₂-C₆)-Alkenyl and (C₂-C₄)-alkenyl are in the context of the inventiona straight-chain or branched alkenyl radical having respectively 2 to 6and 2 to 4 carbon atoms and one or two double bonds. A straight-chain orbranched alkenyl radical having 2 to 4 carbon atoms and one double bondis preferred. Examples which may be preferably mentioned are: vinyl,allyl, isopropenyl and n-but-2-en-1-yl.

(C₂-C₄)-Alkynyl is in the context of the invention a straight-chain orbranched alkynyl radical having 2 to 4 carbon atoms and a triple bond. Astraight-chain alkynyl radical having 2 to 4 carbon atoms is preferred.Examples which may be preferably mentioned are: ethynyl,n-prop-1-yn-1-yl, n-prop-2-yn-1-yl, n-but-1-yn-1-yl, n-but-2-yn-1-yl andn-but-3-yn-1-yl.

(C₁-C₆)-Alkoxy and (C₁-C₄)-alkoxy are in the context of the invention astraight-chain or branched alkoxy radical having respectively 1 to 6 and1 to 4 carbon atoms. A straight-chain or branched alkoxy radical having1 to 4 carbon atoms is preferred. Examples which may be preferablymentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,tert-butoxy, n-pentoxy and n-hexoxy.

(C₁-C₆)-Alkylthio and (C₁-C₄)-alkylthio are in the context of theinvention a straight-chain or branched alkylthio radical havingrespectively 1 to 6 and 1 to 4 carbon atoms. A straight-chain orbranched alkylthio radical having 1 to 4 carbon atoms is preferred.Examples which may be preferably mentioned are: methylthio, ethylthio,n-propylthio, isopropylthio, n-butylthio, tert-butylthio, n-pentylthioand n-hexylthio.

Mono-(C₁-C₆)-alkylamino and mono-(C₁-C₄)-alkylamino are in the contextof the invention an amino group having one straight-chain or branchedalkyl substituent which has respectively 1 to 6 and 1 to 4 carbon atoms.A straight-chain or branched monoalkylamino radical having 1 to 4 carbonatoms is preferred. Examples which may be preferably mentioned are:methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino,tert-butylamino, n-pentylamino and n-hexylamino

Di-(C₁-C₆)-alkylamino and di-(C₁-C₄)-alkylamino are in the context ofthe invention an amino group having two identical or differentstraight-chain or branched alkyl substituents each having respectively 1to 6 and 1 to 4 carbon atoms. Straight-chain or branched dialkylaminoradicals each having 1 to 4 carbon atoms are preferred. Examples whichmay be preferably mentioned are: N,N-dimethylamino, N,N-diethylamino,N-ethyl-N-methylamino, N-methyl-N-n-propylamino,N-isopropyl-N-n-propylamino, N,N-diisopropylamino,N-n-butyl-N-methylamino, N-tert-butyl-N-methylamino,N-methyl-N-n-pentylamino and N-n-hexyl-N-methylamino.

(C₁-C₆)-Acyl and (C₁-C₄)-acyl [(C₁-C₆)-alkanoyl and (C₁-C₄)-alkanoyl]are in the context of the invention a straight-chain or branched alkylradical having respectively 1 to 6 and 1 to 4 carbon atoms which has adoubly bonded oxygen atom in position 1 and is linked via position 1. Anacyl radical having 1 to 4 carbon atoms is preferred. Examples which maybe preferably mentioned are: formyl, acetyl, propionyl, n-butyryl,iso-butyryl, n-pentanoyl, pivaloyl and n-hexanoyl.

(C₁-C₆)-Acylamino and (C₁-C₄)-acylamino are in the context of theinvention an amino group having one straight-chain or branched acylsubstituent which has respectively 1 to 6 and 1 to 4 carbon atoms and islinked via the carbonyl group to the N atom. Examples which may bepreferably mentioned are: formylamino, acetylamino, propionylamino,n-butyrylamino, iso-butyrylamino and pivaloylamino.

(C₁-C₆)-Acyloxy and (C₁-C₄)-acyloxy are in the context of the inventiona straight-chain or branched alkyl radical having respectively 1 to 6and 1 to 4 carbon atoms which has a doubly bonded oxygen atom inposition 1 and is linked via a further oxygen atom in position 1.Examples which may be preferably mentioned are: acetoxy, propionoxy,n-butyroxy, iso-butyroxy and pivaloyloxy.

(C₁-C₆)-Alkoxycarbonyl and (C₁-C₄)-alkoxycarbonyl are in the context ofthe invention a straight-chain or branched alkoxy radical havingrespectively 1 to 6 and 1 to 4 carbon atoms which is linked via acarbonyl group. A straight-chain or branched alkoxycarbonyl radicalhaving 1 to 4 carbon atoms in the alkoxy group is preferred. Exampleswhich may be preferably mentioned are: methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl andtert-butoxycarbonyl.

(C₁-C₆)-Alkoxycarbonylamino and (C₁-C₄)-alkoxycarbonylamino are in thecontext of the invention an amino group having one straight-chain orbranched alkoxycarbonyl substituent which has respectively 1 to 6 and 1to 4 carbon atoms and is linked via the carbonyl group to the N atom.Examples which may be preferably mentioned are: methoxycarbonylamino,ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino,n-butoxycarbonylamino and tert-butoxy-carbonylamino.

Mono- or di-(C₁-C₆)-alkylaminocarbonyl and mono- ordi-(C₁-C₄)-alkylaminocarbonyl are in the context of the invention anamino group which is linked via a carbonyl group and which has onestraight-chain or branched, or two identical or different straight-chainor branched, alkyl substituents each having respectively 1 to 6 and 1 to4 carbon atoms. A mono- or dialkylaminocarbonyl radical having 1 to 4carbon atoms in the alkyl group is preferred. Examples which maypreferably be mentioned are: methylaminocarbonyl, ethylaminocarbonyl,n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl,tert-butylaminocarbonyl, N,N-dimethylaminocarbonyl,N,N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl,N-methyl-N-n-propylaminocarbonyl, N-n-butyl-N-methylaminocarbonyl andN-tert-butyl-N-methylaminocarbonyl.

(C₃-C₈)-Cycloalkyl, (C₃-C₇)-cycloalkyl, (C₃-C₆)-cycloalkyl and(C₅-C₇)-cycloalkyl are in the context of the invention a monocyclic,saturated carbocycle having respectively 3 to 8, 3 to 7, 3 to 6 and 5 to7 ring carbon atoms. Examples which may be preferably mentioned are:cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl.

(C₃-C₈)-Cycloalkenyl and (C₃-C₇)-cycloalkenyl are in the context of theinvention a monocyclic carbocycle having respectively 3 to 8 and 3 to 7ring carbon atoms and one double bond. Examples which may be preferablymentioned are: cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyland cyclooctenyl.

(C₆-C₁₀)-Aryl is in the context of the invention an aromatic carbocyclehaving 6 or 10 ring carbon atoms. Preferred aryl radicals are phenyl andnaphthyl.

5- to 10-membereed heteroaryl is in the context of the invention a mono-or, where appropriate, bicyclic aromatic heterocycle (heteroaromatic)having a total of 5 to 10 ring atoms which comprises up to threeidentical or different ring heteroatoms from the series N, O and/or Sand is linked via a ring carbon atom or, where appropriate, via a ringnitrogen atom. Examples which may be mentioned are: furyl, pyrrolyl,thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl,pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl,benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,benzotriazolyl, indolyl, indazolyl, quinolinyl, isoquinolinyl,naphthyridinyl, quinazolinyl, quinoxalinyl, phthalazinyl,pyrazolo[3,4-b]pyridinyl. Monocyclic 5- or 6-membered heteroarylradicals having up to three ring heteroatoms from the series N, O and/orS are preferred, such as, for example, furyl, thienyl, thiazolyl,oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl,oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl,triazinyl.

A 4- to 8-membered heterocycle is in the context of the invention amonocyclic, saturated heterocycle having a total of 4 to 8 ring atomswhich comprises one or two ring heteroatoms from the series N, O, S, SOand/or SO₂ and is linked via a ring carbon atom or, where appropriate, aring nitrogen atom. A 5- to 7-membered heterocycle having one or tworing heteroatoms from the series N, O and/or S is preferred, and a 5- or6-membered heterocycle having one or two ring heteroatoms from theseries N and/or O is particularly preferred. Examples which may bementioned are: azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl,tetrahydrofuranyl, thiolanyl, piperidinyl, piperazinyl,tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl,hexahydroazepinyl and hexahydro-1,4-diazepinyl. Pyrrolidinyl,tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl andmorpholinyl are preferred.

An unsaturated or aromatic 5- or 6-membered heterocycle is in thecontext of the invention a monocyclic heterocycle having a total of 5 or6 ring atoms which comprises up to four ring heteroatoms from the seriesN, O and/or S, is linked via a ring carbon atom or, where appropriate, aring nitrogen atom, and in the case of the five-membered ring contains adouble bond or is aromatic, and in the case of the 6-membered ringcontains one or two double bonds or is aromatic. Examples which may bementioned are: pyrrolinyl, dihydropyrazolyl, imidazolinyl,dihydrooxazolyl, dihydroisoxazolyl, dihydro-1,2,4-triazolyl,dihydro-1,2,4-oxadiazolyl, dihydro-1,3,4-oxadiazolyl,dihydro-1,2,4-thiadiazolyl, dihydropyranyl, 1,4-dihydropyridyl,tetrahydropyrimidinyl, 1,3-oxazinyl, furyl, pyrrolyl, thienyl,pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl,pyridazinyl, pyrazinyl, triazinyl.

Halogen in the context of the invention includes fluorine, chlorine,bromine and iodine. Fluorine or chlorine are preferred.

If radicals in the compounds according to the invention are substituted,the radicals may, unless otherwise specified, be substituted one or moretimes. In the context of the present invention, all radicals which occurmore than once have a mutually independent meaning. Substitution by one,two or three identical or different substituents is preferred.Substitution by one substituent is very particularly preferred.

Preference is given in the context of the present invention to compoundsof the formula (I) in which

-   -   L is phenyl or thienyl, each of which may be substituted up to        twice, identically or differently, by fluorine, chlorine, cyano,        methyl and/or trifluoromethyl,        -   or        -   is cyclohexyl or cycloheptyl, each of which may be            substituted up to twice, identically or differently, by            fluorine and/or methyl,    -   M is a bicyclic heteroaryl group of the formula (b), (d), (e) or        (h)

-   -   -   in which        -   * is the point of linkage to the —CH₂-L group,        -   ** is the point of linkage to the Q group,        -   A, B and D are each CH, CR¹ or N, with a maximum of two of            the ring members A, B and D simultaneously being N and in            which        -   R¹ is a substituent selected from the series fluorine,            chlorine, bromine, cyano, (C₁-C₄)-alkyl, trifluoromethyl,            amino, (C₁-C₄)-alkoxy and trifluoromethoxy,            -   where, in the event that the substituent R¹ occurs more                than once, its meanings may be identical or different,        -   and        -   E is O or S,

and

-   -   Q is a group of the formula

-   -   -   in which        -   # is the point of linkage to the M group,        -   G is CH or N,        -   J is CR⁷ or N,        -   Z is O or S,        -   R⁵, R⁶ and R⁷ are identical or different and are            independently of one another a radical selected from the            group consisting of halogen, nitro, cyano, —R², —C(═O)—R²,            —C(═O)—OR², —C(═O)—NR²R³, —O—(C═O)_(n)—R², —O—C(═O)—OR²,            —O—C(═O)—NR²R³, —S(O)_(p)—R², —SO₂—OR², —SO₂—NR²R³,            —NR²—(C═O)_(n)—R³, —NR²—SO₂—R³, —NR²—C(═O)—OR³,            —NR⁴—C(═O)—NR²R³ and —NR⁴—SO₂—NR²R³, in which            -   n is the number 0 or 1,            -   p is the number 0 or 2,            -   R², R³ and R⁴ are identical or different and are                independently of one another hydrogen, (C₁-C₆)-alkyl,                (C₂-C₆)-alkenyl, (C₃-C₇)-cycloalkyl,                (C₃-C₇)-cycloalkenyl, phenyl, 5- to 7-membered                heterocyclyl or 5- or 6-membered heteroaryl,            -   and/or            -   R² and R³ or R² and R⁴ together with the radical to                which they are both respectively bonded may form a 5- to                7-membered heterocycle,                -   where R², R³ and R⁴ in turn may optionally be                    substituted up to three times, identically or                    differently, by radicals selected from the group                    consisting of fluorine, chlorine, cyano,                    (C₁-C₄)-alkyl, trifluoromethyl, hydroxy,                    (C₁-C₄)-alkoxy, trifluoromethoxy, oxo, amino,                    mono-(C₁-C₄)-alkylamino and di-(C₁-C₄)-alkylamino,        -   R⁸ is hydrogen, (C₁-C₆)-alkyl or (C₃-C₇)-cycloalkyl,            -   where (C₁-C₆)-alkyl may be substituted up to five times                by fluorine and up to twice, identically or differently,                by (C₃-C₇)-cycloalkyl, hydroxy, (C₁-C₄)-alkoxy,                trifluoromethoxy, (C₁-C₄)-acyloxy, amino,                mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino,                (C₁-C₄)-acylamino, hydroxycarbonyl,                (C₁-C₄)-alkoxycarbonyl, aminocarbonyl,                mono-(C₁-C₄)-aminocarbonyl,                di-(C₁-C₄)-alkylaminocarbonyl and/or a 5- or 6-membered                heterocycle,        -   R⁹ is (C₁-C₄)-alkyl which may be substituted by hydroxy,            (C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino,            di-(C₁-C₄)-alkylamino or up to three times by fluorine,        -   R¹⁰ has the meaning indicated above for R⁸,        -   and        -   R¹¹ is hydrogen or (C₁-C₄)-alkyl,

and the N-oxides, salts, solvates, salts of the N-oxides and solvates ofthe N-oxides and salts thereof.

Particular preference is given in the context of the present inventionto compounds of the formula (I) in which

L is phenyl which may be substituted up to twice by fluorine,

M is a bicyclic heteroaryl group of the formula

-   -   in which    -   * is the point of linkage to the —CH₂-L group    -   and    -   ** is the point of linkage to the Q group,

and

Q is a group of the formula

-   -   in which    -   # is the point of linkage to the M group,    -   J is CR⁷ or N,    -   R⁵ and R⁶ are independently of one another hydrogen or amino,    -   R⁷ is hydrogen, fluorine, chlorine, bromine, (C₁-C₄)-alkyl,        (C₃-C₆)-cycloalkyl, pyridyl or —NR¹²R¹³, in which        -   R¹² is hydrogen or (C₁-C₄)-alkyl which may be substituted by            hydroxy, methoxy or up to three times by fluorine,        -   R¹³ is hydrogen, (C₁-C₄)-alkyl which may be substituted by            hydroxy, methoxy or up to three times by fluorine, or            (C₁-C₄)-acyl, (C₁-C₄)-alkoxycarbonyl or mono- or            di-(C₁-C₄)-alkylaminocarbonyl,        -   or        -   R¹² and R¹³ together with the nitrogen atom to which they            are bonded form a 5- to 7-membered heterocycle which may be            substituted by oxo,    -   and    -   R⁸ is hydrogen or (C₁-C₄)-alkyl which may be substituted up to        three times by fluorine,

and the N-oxides, salts, solvates, salts of the N-oxides and solvates ofthe N-oxides and salts thereof.

The definitions of radicals indicated specifically in their respectivecombinations or preferred combinations of radicals are replaced asdesired irrespective of the particular combinations indicated for theradicals also by definitions of radicals of other combinations.

Combinations of two or more of the abovementioned preferred ranges areparticularly preferred.

Very particular preference is given to the compound6-[1-(2-fluorobenzyl)-1H-imidazo[2,1-c][1,2,4]triazol-3-yl]-1,3,5-triazin-2,4-diamineand the N-oxides, salts, solvates, salts of the N-oxides and solvates ofthe N-oxides and salts thereof.

The compounds of the invention of the formula (I) can be prepared inanalogy to methods described in the literature for example by

[A] Condensing a Compound of the Formula (II)

-   -   in which A, B, D and L each have the meanings indicated above,        and    -   T is (C₁-C₄)-alkyl,    -   with a compound of the formula (III)

-   -   in which J, R⁵ and R⁶ each have the meanings indicated above,    -   to give a compound of the formula (I-A)

-   -   in which A, B, D, J, L, R⁵ and R⁶ each have the meanings        indicated above,

or

[B] Reacting a Compound of the Formula (IV)

-   -   in which A, B, D and L each have the meanings indicated above,    -   with a compound of the formula (V)

-   -   in which J and R⁶ have the meanings indicated above,    -   to give a compound of the formula (I-B)

-   -   in which A, B, D, J, L and R⁶ each have the meanings indicated        above,

or

[C] Converting a Compound of the Formula (VI)

-   -   in which A, B, E and L each have the meanings indicated above,    -   with a compound of the formula (VII)

-   -   in which G, J, R⁵ and R⁶ each have the meanings indicated above,        and    -   X is a suitable leaving group such as, for example, halogen,        mesylate, tosylate or triflate,    -   into a compound of the formula (I-C)

-   -   in which A, B, E, G, J, L, R⁵ and R⁶ each have the meanings        indicated above,

or

[D] Reacting a Compound of the Formula (VIII)

-   -   in which A, B, D and L each have the meanings indicated above,    -   with a compound of the formula (IXa), (IXb), (IXc) or (IXd)

-   -   in which R⁷ and T have the meanings indicated previously, and    -   Y is amino, mono- or di-(C₁-C₄)-alkylamino, piperidino,        morpholino, hydroxy, (C₁-C₄)-alkoxy or (C₁-C₄)-acyloxy,    -   to give a compound of the formula (I-D), (I-E), (I-F) or (I-G)

-   -   in which A, B, D, L and R⁷ each have the meanings indicated        above,

or

[E] Converting a Compound of the Formula (IV)

-   -   in which A, B, D and L each have the meanings indicated above,    -   with an alkali metal azide in the presence of an acid or with        trimethylsilyl azide in the presence of a catalyst such as        dibutyltin oxide into a compound of the formula (I-H)

-   -   in which A, B, D and L each have the meanings indicated above,

or

[F] Firstly Converting a Compound of the Formula (IV)

-   -   in which A, B, D and L each have the meanings indicated above,    -   with hydroxylamine into a compound of the formula (X)

-   -   in which A, B, D and L each have the meanings indicated above,        and then reacting the latter with phosgene or a phosgene        equivalent such as N,N′-carbonyl-diimidazole or a chloroformate        to give a compound of the formula (I-J)

-   -   in which A, B, D and L each have the meanings indicated above,

or

[G] Firstly Converting a Compound of the Formula (II)

-   -   in which A, B, D, L and T each have the meanings indicated        above,    -   with hydrazide into a compound of the formula (XI)

-   -   in which A, B, D and L each have the meanings indicated above,    -   and then reacting the latter with phosgene or a phosgene        equivalent such as N,N′-carbonyl-diimidazole or a chloroformate        to give a compound of the formula (I-K)

-   -   in which A, B, D, and L each have the meanings indicated above,

where appropriate modifying the resulting compounds of the formulae(I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-J) and (I-K)by processes customary in the literature further in the scope indicatedabove of the meanings of the individual substituents and radicals,

and converting the compounds of the invention obtained in this way whereappropriate with the appropriate (i) solvents and/or (ii) acids or basesinto the solvates, salts and/or solvates of the salts thereof.

The compounds of the formulae (II), (IV), (VI) and (VIII) can beprepared in analogy to methods known from the literature starting fromcompounds which are commercially available or described in theliterature (cf. reaction schemes 1-7 below). The compounds of theformulae (III), (V), (VII), (IXa), (IXb), (IXc) and (IXd) arecommercially available, known from the literature or can be prepared bymethods customary in the literature.

The preparation of the compounds of the invention can be illustrated byway of example by the following synthesis scheme:

The compounds of the invention have valuable pharmacological propertiesand can be used for the prevention and treatment of disorders in humansand animals. The compounds of the invention open up a further treatmentalternative and represent an enrichment of pharmacy.

The compounds of the invention have a vasorelaxant and plateletaggregation-inhibiting effect and lead to a reduction in blood pressureand to an increase in the coronary blood flow. These effects aremediated by a direct stimulation of soluble guanylate cyclase and anintracellular increase in cGMP.

In addition, the compounds of the invention enhance the effect ofsubstances which increase the cGMP level, such as, for example, EDRF(endothelium-derived relaxing factor), NO donors, protoporphyrin IX,arachidonic acid or phenylhydrazine derivatives.

The compounds according to the invention can therefore be employed inmedicaments for the treatment of cardiovascular disorders such as, forexample, for the treatment of high blood pressure and heart failure,stable and unstable angina pectoris, pulmonary hypertension, peripheraland cardiac vascular disorders, arrhythmias, for the treatment ofthromboembolic disorders and ischemias such as myocardial infarction,stroke, transistoric and ischemic attacks, disturbances of peripheralblood flow, reperfusion damage, for the prevention of restenoses asafter thrombolysis therapies, percutaneous transluminal angioplasties(PTA), percutaneous transluminal coronary angioplasties (PTCA) andbypass and for the treatment of arteriosclerosis, asthmatic disordersand diseases of the urogenital system such as, for example, prostatehypertrophy, erectile dysfunction, female sexual dysfunction, andincontinence, osteoporosis, glaucoma, and gastroparesis.

The compounds according to the invention can additionally be used forthe treatment of primary and secondary Raynaud's phenomenon, ofmicrocirculation impairments, claudication, peripheral and autonomicneuropathies, diabetic microangiopathies, diabetic retinopathy, diabeticulcers on the extremities, gangrene, CREST syndrome, erythematosis,onychomycosis, rheumatic disorders, and for promoting wound healing.

The compounds according to the invention are furthermore suitable forthe treatment of acute and chronic pulmonary diseases such asrespiratory distress syndromes (ALI, ARDS) and chronic obstructiveairway disorders (COPD), and for treating acute and chronic renalfailure.

The compounds described in the present invention also represent activeingredients for controlling central nervous system diseasescharacterized by disturbances of the NO/cGMP system. They are suitablein particular for improving perception, concentration, learning ormemory after cognitive impairments like those occurring in particular inassociation with situations/diseases/syndromes such as mild cognitiveimpairment, age-associated learning and memory impairments,age-associated memory losses, vascular dementia, craniocerebral trauma,stroke, dementia occuring after strokes (post-stroke dementia),post-traumatic craniocerebral trauma, general concentration impairments,concentration impairments in children with learning and memory problems,Alzheimer's disease, Lewy body dementia, dementia with degeneration ofthe frontal lobes including Pick's syndrome, Parkinson's disease,progressive nuclear palsy, dementia with corticobasal degeneration,amyolateral sclerosis (ALS), Huntington's disease, multiple sclerosis,thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia,schizophrenia with dementia or Korsakoff's psychosis. They are alsosuitable for the treatment of central nervous system disorders such asstates of anxiety, tension and depression, CNS-related sexualdysfunctions and sleep disorders, and for controlling pathologicaldisturbances of the intake of food, stimulants and addictive substances.

The compounds according to the invention are furthermore also suitablefor controlling cerebral blood flow and thus represent effective agentsfor controlling migraine. They are also suitable for the prophylaxis andcontrol of the sequelae of cerebral infarctions such as stroke, cerebralischemias and craniocerebral trauma. The compounds according to theinvention can likewise be employed for controlling states of pain.

In addition, the compounds according to the invention have ananti-inflammatory effect and can therefore be employed asanti-inflammatory agents.

The present invention further relates to the use of the compoundsaccording to the invention for the treatment and/or prevention ofdisorders, especially of the aforementioned disorders.

The present invention further relates to the use of the compoundsaccording to the invention for producing a medicament for the treatmentand/or prevention of disorders, especially of the aforementioneddisorders.

The present invention further relates to a method for the treatmentand/or prevention of disorders, especially of the aforementioneddisorders, by using an effective amount of at least one of the compoundsaccording to the invention.

The compounds according to the invention can be employed alone or, ifrequired, in combination with other active ingredients. The presentinvention further relates to medicaments comprising at least one of thecompounds according to the invention and one or more further activeingredients, in particular for the treatment and/or prevention of theaforementioned disorders. Examples of suitable combination activeingredients which may be preferably mentioned are:

-   -   organic nitrates and NO donors such as, for example, sodium        nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide        dinitrate, molsidomine or SIN-1, and inhaled NO;    -   compounds which inhibit the breakdown of cyclic guanosine        monophosphate (cGMP), such as, for example, inhibitors of        phosphodiesterases (PDE) 1, 2 and/or 5, in particular PDE 5        inhibitors such as sildenafil, vardenafil and tadalafil;    -   agents having antithrombotic activity, for example and        preferably from the group of platelet aggregation inhibitors, of        anticoagulants or of profibrinolytic substances;    -   active ingredients which lower blood pressure, for example and        preferably from the group of calcium antagonists, angiotensin        AII antagonists, ACE inhibitors, endothelin antagonists, renin        inhibitors, alpha-receptor blockers, beta-receptor blockers,        mineralocorticoid receptor antagonists, and of diuretics; and/or    -   active ingredients which modify lipid metabolism, for example        and preferably from the group of thyroid receptor agonists,        cholesterol synthesis inhibitors such as, for example and        preferably, HMG-CoA reductase inhibitors or squalene synthesis        inhibitors, of ACAT inhibitors, CETP inhibitors, MTP inhibitors,        PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol        absorption inhibitors, lipase inhibitors, polymeric bile acid        adsorbents, bile acid reabsorption inhibitors and        lipoprotein (a) antagonists.

Agents having antithrombotic activity preferably mean compounds from thegroup of platelet aggregation inhibitors, of anticoagulants or ofprofibrinolytic substances.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a plateletaggregation inhibitor such as, for example and preferably, aspirin,clopidogrel, ticlopidine or dipyridamole.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a thrombin inhibitorsuch as, for example and preferably, ximelagatran, melagatran,bivalirudin or clexane.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a GPIIb/IIIaantagonist such as, for example and preferably, tirofiban or abciximab.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a factor Xa inhibitorsuch as, for example and preferably, rivaroxaban (BAY 59-7939), DU-176b,apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux,PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC906, JTV 803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with heparin or with a lowmolecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a vitamin Kantagonist such as, for example and preferably, coumarin.

Agents which lower blood pressure preferably mean compounds from thegroup of calcium antagonists, angiotensin AII antagonists, ACEinhibitors, endothelin antagonists, renin inhibitors, alpha-receptorblockers, beta-receptor blockers, mineralocorticoid receptorantagonists, and of diuretics.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a calcium antagonistsuch as, for example and preferably, nifedipine, amlodipine, verapamilor diltiazem.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an alpha-1-receptorblocker such as, for example and preferably, prazosin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a beta-receptorblocker such as, for example and preferably, propranolol, atenolol,timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol,metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol,betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol,carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an angiotensin AIIantagonist such as, for example and preferably, losartan, candesartan,valsartan, telmisartan or embursatan.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an ACE inhibitor suchas, for example and preferably, enalapril, captopril, lisinopril,ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an endothelinantagonist such as, for example and preferably, bosentan, darusentan,ambrisentan or sitaxsentan.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a renin inhibitorsuch as, for example and preferably, aliskiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a mineralocorticoidreceptor antagonist such as, for example and preferably, spironolactoneor eplerenone.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a diuretic such as,for example and preferably, furosemide.

Agents which modify lipid metabolism preferably mean compounds from thegroup of CETP inhibitors, thyroid receptor agonists, cholesterolsynthesis inhibitors such as HMG-CoA reductase inhibitors or squalenesynthesis inhibitors, of ACAT inhibitors, MTP inhibitors, PPAR-alpha,PPAR-gamma and/or PPAR-delta agonists, cholesterol absorptioninhibitors, polymeric bile acid adsorbents, bile acid reabsorptioninhibitors, lipase inhibitors and of lipoprotein(a) antagonists.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a CETP inhibitor suchas, for example and preferably, torcetrapib (CP-529 414), JJT-705 orCETP vaccine (Avant).

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a thyroid receptoragonist such as, for example and preferably, D-thyroxine,3,5,3′-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an HMG-CoA reductaseinhibitor from the class of statins such as, for example and preferably,lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin,rosuvastatin, cerivastatin or pitavastatin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a squalene synthesisinhibitor such as, for example and preferably, BMS-188494 or TAK-475.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an ACAT inhibitorsuch as, for example and preferably, avasimibe, melinamide, pactimibe,eflucimibe or SMP-797.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an MTP inhibitor suchas, for example and preferably, implitapide, BMS-201038, R-103757 orJTT-130.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a PPAR-gamma agonistsuch as, for example and preferably, pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a PPAR-delta agonistsuch as, for example and preferably, GW 501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a cholesterolabsorption inhibitor such as, for example and preferably, ezetimibe,tiqueside or pamaqueside.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a lipase inhibitorsuch as, for example and preferably, orlistat.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a polymeric bile acidadsorbent such as, for example and preferably, cholestyramine,colestipol, colesolvam, CholestaGel or colestimide.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a bile acidreabsorption inhibitor such as, for example and preferably, ASBT (=IBAT)inhibitors such as, for example, AZD-7806, S-8921, AK-105, BARI-1741,SC-435 or SC-635.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a lipoprotein (a)antagonist such as, for example and preferably, gemcabene calcium(CI-1027) or nicotinic acid.

The present invention further relates to medicaments which comprise atleast one compound according to the invention, normally together withone or more inert, non-toxic, pharmaceutically suitable excipients, andto the use thereof for the aforementioned purposes.

The compounds according to the invention can act systemically and/orlocally. For this purpose, they can be administered in a suitable waysuch as, for example, by the oral, parenteral, pulmonal, nasal,sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival,otic route or as implant or stent.

The compounds according to the invention can be administered inadministration forms suitable for these administration routes.

Suitable for oral administration are administration forms which functionaccording to the prior art and deliver the compounds according to theinvention rapidly and/or in modified fashion, and which contain thecompounds according to the invention in crystalline and/or amorphizedand/or dissolved form, such as, for example, tablets (uncoated or coatedtablets, for example having enteric coatings or coatings which areinsoluble or dissolve with a delay and control the release of thecompound according to the invention), tablets which disintegrate rapidlyin the mouth, or films/wafers, films/lyophilizates, capsules (forexample hard or soft gelatin capsules), sugar-coated tablets, granules,pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can take place with avoidance of an absorptionstep (e.g. intravenous, intraarterial, intracardiac, intraspinal orintralumbar) or with inclusion of an absorption (e.g. intramuscular,subcutaneous, intracutaneous, percutaneous or intraperitoneal).Administration forms suitable for parenteral administration are, interalia, preparations for injection and infusion in the form of solutions,suspensions, emulsions, lyophilizates or sterile powders.

Suitable for the other administration routes are, for example,pharmaceutical forms for inhalation (inter alia powder inhalers,nebulizers), nasal drops, solutions or sprays, tablets for lingual,sublingual or buccal administration, films/wafers or capsules,suppositories, preparations for the ears or eyes, vaginal capsules,aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions,ointments, creams, transdermal therapeutic systems (e.g. patches), milk,pastes, foams, dusting powders, implants or stents.

Oral or parenteral administration is preferred, especially oraladministration.

The compounds according to the invention can be converted into thestated administration forms. This can take place in a manner known perse by mixing with inert, non-toxic, pharmaceutically suitableexcipients. These excipients include, inter alia, carriers (for examplemicrocrystalline cellulose, lactose, mannitol), solvents (e.g. liquidpolyethylene glycols), emulsifiers and dispersants or wetting agents(for example sodium dodecyl sulfate, polyoxysorbitan oleate), binders(for example polyvinylpyrrolidone), synthetic and natural polymers (forexample albumin), stabilizers (e.g. antioxidants such as, for example,ascorbic acid), colorants (e.g. inorganic pigments such as, for example,iron oxides) and masking flavors and/or odors.

It has generally proved advantageous to administer on parenteraladministration amounts of about 0.001 to 1 mg/kg, preferably about 0.01to 0.5 mg/kg, of body weight to achieve effective results, and on oraladministration the dosage is about 0.01 to 100 mg/kg, preferably about0.01 to 20 mg/kg, and very particularly preferably 0.1 to 10 mg/kg, ofbody weight.

It may nevertheless be necessary where appropriate to deviate from thestated amounts, in particular as a function of the body weight, route ofadministration, individual response to the active ingredient, nature ofthe preparation and time or interval over which administration takesplace. Thus, it may be sufficient in some cases to make do with lessthan the aforementioned minimum amount, whereas in other cases thestated upper limit must be exceeded. It may in the event ofadministration of larger amounts be advisable to divide these into aplurality of individual doses over the day.

The following exemplary embodiments illustrate the invention. Theinvention is not restricted to the examples.

The percentage data in the following tests and examples are, unlessindicated otherwise, percentages by weight; parts are parts by weight.Solvent ratios, dilution ratios and concentration data for theliquid/liquid solutions are in each case based on volume.

A. EXAMPLES

Abbreviations and Acronyms:

aq. aqueous solution

calc. calculated

conc. concentrated

DCI direct chemical ionization (in MS)

DMF dimethylformamide

DMSO dimethyl sulfoxide

eq. equivalent(s)

ESI electrospray ionization (in MS)

Et ethyl

h hour(s)

HPLC high pressure, high performance liquid chromatography

HRMS high resolution mass spectrometry

LC/MS coupled liquid chromatography-mass spectrometry

min minute(s)

MS mass spectrometry

NMR nuclear magnetic resonance spectrometry

RT room temperature

R_(t) retention time (in HPLC)

THF tetrahydrofuran

UV ultraviolet spectrometry

v/v volume to volume ratio (of a solution)

LC/MS Methods:

Method 1 (LC/MS):

MS instrument type: Micromass ZQ; HPLC instrument type: HP 1100 Series;UV DAD; column: Phenomenex Gemini 3μ 30 mm×3.00 mm; eluent A: 1 lwater+0.5 ml 50% formic acid, eluent B: 1 l acetonitrile+0.5 ml 50%formic acid; gradient: 0.0 min 90% A→2.5 min 30% A→3.0 min 5% A→4.5 min5% A; flow rate: 0.0 min 1 ml/min→2.5 min/3.0 min/4.5 min 2 ml/min;oven: 50° C.; UV detection: 210 nm.

Method 2 (LC/MS):

MS instrument type: Micromass ZQ; HPLC instrument type: Waters Alliance2795; column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm×4 mm; eluentA: 1 l water+0.5 ml 50% formic acid, eluent B: 1 l acetonitrile+0.5 ml50% formic acid; gradient: 0.0 min 90% A→2.5 min 30% A→3.0 min 5% A→4.5min 5% A; flow rate: 0.0 min 1 ml/min→2.5 min/3.0 min/4.5 min 2 ml/min;oven: 50° C.; UV detection: 210 nm.

Method 3 (LC/MS):

Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; column:Phenomenex Onyx Monolithic C18, 100 mm×3 mm; eluent A: 1 l water+0.5 ml50% formic acid, eluent B: 1 l acetonitrile+0.5 ml 50% formic acid;gradient: 0.0 min 90% A→2 min 65% A→4.5 min 5% A→6 min 5% A; flow rate:2 ml/min; oven: 40° C.; UV detection: 208-400 nm.

Starting Compounds and Intermediates:

Example 1A Ethyl (2E)-[(2-fluorobenzyl)hydrazono]acetate

(2-Fluorobenzyl)hydrazine (1.00 g, 7.14 mmol) is suspended in water (3ml), and the mixture is brought to pH 4 with 4N hydrochloric acid. It isthen cooled in an ice bath, and a solution of ethylchloro(ethoxy)acetate (1.37 g, 8.21 mmol) in dioxane (10 ml) is added.The mixture is stirred at RT for 1 h, then made weakly alkaline (pH 8)with 1N sodium hydroxide solution and extracted with ethyl acetate. Theorganic phase is dried over sodium sulfate. The crude product ispurified by chromatography on silica gel (eluent: dichloromethane withincreasing methanol content). 1.40 g (88% of theory) of the desiredcompound are obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.19 (t, J=7.1 Hz, 3H), 4.09 (q, J=7.1 Hz,2H), 4.42 (d, J=4.4 Hz, 2H), 6.74 (s, 1H), 7.18-7.24 (m, 2H), 7.31-7.40(m, 2H), 9.18 (t, J=4.4 Hz, 1H).

¹³C-NMR (125 MHz, DMSO-d₆): δ=14.2, 44.2 (br), 59.2, 115.3 (d,²J_(C,F)=21.1 Hz), 119.3 (br), 123.2 (br), 124.4 (d, ⁴J_(C,F)=3.4 Hz),129.6 (d, ³J_(C,F)=8.2 Hz), 130.2 (d, ³J_(C,F)=4.2 Hz), 160.2 (d,¹J_(C,F)=245 Hz), 164.1.

HRMS: calc. for C₁₁H₁₃FN₂O₂ 224.0961; found 224.0962.

LC/MS (Method 2): R_(t)=1.83 min; MS (ESIpos): m/z=225 [M+H]⁺.

Example 2A Ethyl (2Z)-chloro[(2-fluorobenzyl)hydrazono]acetate

Ethyl (2E)-[(2-fluorobenzyl)hydrazono]acetate (300 mg, 1.14 mmol) fromexample 1A are dissolved in ethyl acetate (2.0 ml). N-Chlorosuccinimide(143 mg, 1.07 mmol) is added, and the mixture is stirred at 60° C. for 1h. It is then concentrated in vacuo, and the residue is stirred withcarbon tetrachloride. The filtrate after filtration is concentrated. 292mg (82% of theory) of the desired compound are obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.22 (t, J=7.1 Hz, 3H), 4.19 (q, J=7.1 Hz,2H), 4.60 (d, J=4.4 Hz, 2H), 7.16-7.22 (m, 2H), 7.28-7.37 (m, 2H), 8.69(t, J=4.4 Hz, 1H).

¹³C-NMR (125 MHz, DMSO-d₆): δ=14.2, 46.7 (d, ³J_(C,F)=3.9 Hz), 61.8,111.1, 115.3 (d, ²J_(C,F)=21.1 Hz), 124.5 (d, ⁴J_(C,F)=3.4 Hz), 125.8(d, ²J_(C,F)=14.6 Hz), 129.4 (d, ³H_(C,F)=8.1 Hz), 129.8 (d,³J_(C,F)=4.3 Hz), 159.4, 159.9 (d, ¹J_(C,F)=245 Hz).

HRMS: calc. for C₁₁H₁₂ClFN₂O₂ 258.0571; found 258.0571.

LC/MS (Method 2): R_(t)=2.21 min; MS (ESIpos): m/z=259 [M+H]⁺.

Example 3A Ethyl1-(2-fluorobenzyl)-1H-imidazo[2,1-c][1,2,4]triazole-3-carboxylate

Ethyl (2Z)-chloro[(2-fluorobenzyl)hydrazono]acetate (750 mg, 2.90 mmol)from example 2A, 2-allylthio-1H-imidazole [U.S. Pat. No. 3,574,593;Chem. Abstr. 75, 49078] (1.20 g, 7.25 mmol) and triethylamine (293 mg,2.90 mmol) are dissolved in dioxane (10 ml) and heated under reflux for4 h. This is followed by dilution with water and extraction with ethylacetate. The organic phase is dried over sodium sulfate, and the crudeproduct is purified by chromatography on silica gel (eluent:dichloromethane/methanol 50:1). 410 mg (41% of theory) of the desiredproduct are obtained with 84% purity.

¹H-NMR (500 MHz, DMSO-d₆): δ=1.35 (t, J=7.1 Hz, 3H), 4.41 (q, J=7.1 Hz,2H), 5.52 (s, 2H), 7.19-7.28 (m, 2H), 7.29 (s, 1H), 7.39-7.46 (m, 2H),7.52 (s, 1H).

¹³ C-NMR (125 MHz, DMSO-d₆): δ=14.0, 46.0 (d, ³J_(C,F)=3.7 Hz), 62.1,107.5, 115.6 (d, ²J_(C,F)=20.8 Hz), 122.0 (d, ²J_(C,F)=14.8 Hz), 124.7(d, ⁴J_(C,F)=3.7 Hz), 129.0, 130.7 (d, ³J_(C,F)=8.1 Hz), 131.0 (d,³J_(C,F)=3.7 Hz), 136.7, 151.0, 156.2, 160.2 (d, ¹J_(C,F)=247 Hz).

HRMS: calc. for C₁₄H₁₃FN₄O₂ 288.1023; found 288.1021.

LC/MS (Method 1): R_(t)=2.16 min; MS (ESIpos): m/z=289 [M+H]⁺.

Example 4A Ethyl1-(2-fluorobenzyl)-1H-[1,2,4]triazolo[3,4-c][1,2,4]triazole-3-carboxylate

Ethyl(2Z)-chloro[(2-fluorobenzyl)hydrazono]acetate (807 mg, 3.12 mmol)from example 2A, 5-(methylthio)-1H-1,2,4-triazole (359 mg, 3.12 mmol)and triethylamine (316 mg, 3.12 mmol) are dissolved in dioxane (5 ml)and heated under reflux for 6 h. This is followed by dilution with waterand extraction with ethyl acetate. The organic phase is dried oversodium sulfate, and the crude product is purified by chromatography onsilica gel (eluent: dichloromethane/methanol 50:1). 124 mg (9.5% oftheory) of the desired product are obtained with 69% purity.

¹H-NMR (500 MHz, DMSO-d₆): δ=1.35 (t, J=7.1 Hz, 3H), 4.42 (q, J=7.1 Hz,2H), 5.53 (s, 2H), 7.21-7.29 (m, 2H), 7.41-7.52 (m, 2H), 8.86 (s, 1H).

¹³C-NMR (125 MHz, DMSO-d₆): δ=13.9, 46.7 (d, ³J_(C,F)=3.7 Hz), 62.5,115.6 (d, ²J_(C,F)=20.7 Hz), 121.5 (d, ²J_(C,F)=14.7 Hz), 124.7 (d,⁴J_(C,F)=3.5 Hz), 127.8, 130.3, 130.9 (d, ³J_(C,F)=8.1 Hz), 131.2 (d,³J_(C,F)=3.4 Hz), 155.4, 158.2, 160.3 (d, ¹J_(C,F)=247 Hz).

HRMS: calc. for C₁₃H₁₂FN₅O₂ 289.0975; found 289.0963.

LC/MS (Method 1): R_(t)=1.95 min; MS (ESIpos): m/z=290 [M+H]⁺.

Exemplary Embodiments Example 16-[1-(2-Fluorobenzyl)-1H-imidazo[2,1-c][1,2,4]triazol-3-yl]-1,3,5-triazine-2,4-diamine

A methanolic sodium methanolate solution (5.4 N, 0.43 ml, 2.30 mmol) isdiluted with methanol (3 ml). Biguanidine dihydrochloride (170 mg, 0.98mmol) is added, and the mixture is stirred at 50° C. for 30 min. Then asolution of ethyl1-(2-fluorobenzyl)-1H-imidazo[2,1-c][1,2,4]triazole-3-carboxylate (200mg, 84% pure, 0.58 mmol) from example 3A in methanol (3 ml) is added,and the mixture is heated under reflux for 3 h. It is then diluted withwater. The precipitate is filtered off with suction and washed withmethanol. 103 mg (55% of theory) of the title compound are obtained.

¹H-NMR (500 MHz, DMSO-d₆): δ=5.48 (s, 2H), 6.96 (br. s, 2H), 7.16 (br.s, 2H), 7.17-7.27 (m, 3H), 7.38-7.46 (m, 2H), 7.86 (s, 1H).

¹³C-NMR (125 MHz, DMSO-d₆): δ=45.5 (d, ³J_(C,F)=3.5 Hz), 109.0, 115.5(d, ²J_(C,F)=20.8 Hz), 122.5 (d, ²J_(C,F)=14.8 Hz), 124.7 (d,⁴J_(C,F)=3.7 Hz), 130.5 (d, ³J_(C,F)=8.1 Hz), 131.0 (d, ³J_(C,F)=3.7Hz), 135.0, 135.6, 151.1, 160.1 (d, ¹J_(C,F)=247 Hz), 161.3, 166.9.

HRMS: calc. for C₁₄H₁₂FN₉ 325.1200; found 325.1188.

LC/MS (Method 3): R_(t)=1.46 min; MS (ESIpos): m/z=326 [M+H]⁺.

Example 26-[1-(2-Fluorobenzyl)-1H-[1,2,4]triazolo[3,4-c][1,2,4]triazol-3-yl]-1,3,5-triazine-2,4-diamine

A methanolic sodium methanolate solution (5.4 N, 0.47 ml, 2.54 mmol) isdiluted with methanol (3 ml). Biguanidine dihydrochloride (189 mg, 1.08mmol) is added, and the mixture is stirred at 50° C. for 30 min. Then asolution of ethyl1-(2-fluorobenzyl)-1H-[1,2,4]-triazolo-[3,4-c][1,2,4]triazole-3-carboxylate(184 mg, 65% pure, 0.36 mmol) from example 4A in methanol (2 ml) isadded, and the mixture is heated under reflux for 3 h. It is thendiluted with water. The precipitate is filtered off with suction andwashed with methanol. 53 mg (39% of theory) of the title compound areobtained.

¹H-NMR (400 MHz, DMSO-d₆): δ=5.49 (s, 2H), 7.04 (br. s, 2H), 7.19 (br.s, 2H), 7.21-7.29 (m, 2H), 7.40-7.51 (m, 2H), 9.00 (s, 1H).

¹³C-NMR (125 MHz, DMSO-d₆): δ=46.4 (d, ³J_(C,F)=3.2 Hz), 115.6 (d,²J_(C,F)=20.8 Hz), 122.0 (d, ²J_(C,F)=14.8 Hz), 124.7 (d, ⁴J_(C,F)=3.5Hz), 130.8 (d, ³J_(C,F)=8.3 Hz), 131.2 (d, ³J_(C,F)=3.5 Hz), 131.6,133.9, 158.2, 160.3 (d, ^(1l)J_(C,F)=247 Hz), 160.5, 166.9.

HRMS: calc. for C₁₃H₁₁FN₁₀ 326.1152; found 326.1144.

LC/MS (Method 2): R_(t)=1.17 min; MS (ESIpos): m/z=327 [M+H]⁺.

B. ASSESSMENT OF THE PHARMACOLOGICAL ACTIVITY

The pharmacological effect of the compounds of the invention can beshown in the following assays:

B-1. Vasorelaxant Effect In Vitro

Rabbits are stunned by a blow to the back of the neck and areexsanguinated. The aorta is removed, freed of adherent tissue, dividedinto rings 1 5 mm wide and placed singly in 5 ml organ baths withcarbogen-gassed Krebs-Henseleit solution of the following composition(in each case mM): NaCl: 119; KCl: 4.8; CaCl₂×2H₂O: 1; MgSO₄×7H₂O: 1.4;KH₂PO₄: 1.2; NaHCO₃: 25; glucose: 10, under an initial tension at 37° C.The force of contraction is detected with Statham UC2 cells, amplifiedand digitized via A/D converters (DAS-1802 HC, Keithley InstrumentsMunich), and recorded in parallel on chart recorders. A contraction isinduced by adding phenylephrine to the bath cumulatively in increasingconcentration. After several control cycles, the substance to beinvestigated is added in each further run in increasing dosage eachtime, and the level of contraction is compared with the level ofcontraction achieved in the last preceding run. The concentrationnecessary to reduce the level of contraction by 50% (IC₅₀) is calculatedtherefrom. The standard application volume is 5 μl, and the DMSO contentin the bath solution corresponds to 0.1%.

Exemplary embodiment 1 exhibits an IC₅₀ of 6.2 μm in this test.

B-2. Effect on Recombinant Guanylate Cyclase Reporter Cell Line

The cellular effect of the compounds of the invention is determined on arecombinant guanylate cyclase reporter cell line as described in F.Wunder et al., Anal. Biochem. 339, 104-112 (2005).

B-3. Determination of Pharmacokinetic Characteristics after Intravenousand Oral Administration

The substance to be investigated is administered to animals (e.g. mouse,rat, dog) intravenously as solution; oral administration takes place assolution or suspension by gavage. After administration of the substance,blood is taken from the animals at fixed times. This is heparinized andthen plasma is obtained therefrom by centrifugation. The substance isquantified in the plasma analytically by LC/MS-MS. The pharmacokineticcharacteristics such as AUC, C_(max), T_(1/2) (half life) and CL(clearance) are calculated from the plasma concentration-time coursesascertained in this way, by means of a validated pharmacokineticcomputer program.

B-4. Determination of the Solubility

Reagents Required:

-   -   PBS buffer pH 7.4: weigh 90.00 g of NaCl, analytical grade (e.g.        from Merck, Cat. No. 1.06404.1000), 13.61 g of KH₂PO₄ analytical        grade (e.g. from Merck, Cat. No. 1.04873.1000) and 83.35 g of 1        N NaOH (e.g. from Bernd Kraft GmbH, Cat. No. 01030.4000) into a        1 liter graduated flask, make up to the mark with water and stir        for about 1 hour;    -   acetate buffer pH 4.6: weigh 5.4 g of sodium acetate×3H₂O,        analytical grade (e.g. from Merck, Cat. No. 1.06267.0500) into a        100 ml graduated flask, dissolve in 50 ml of water, add 2.4 g of        glacial acetic acid, make up to 100 ml with water, check the pH        and adjust to pH 4.6 if necessary;    -   dimethyl sulfoxide (e.g. from Baker, Cat. No. 7157.2500);    -   distilled water.

Preparation of the Calibration Solutions

Preparation of the starting solution for calibration solutions (stocksolution): About 0.5 mg of the test substance is weighed accurately intoa 2 ml Eppendorf safe-lock tube (from Eppendorf, Cat.

No. 0030 120.094), DMSO is added to a concentration of 600 μg/ml (e.g.0.5 mg of substance+833 μl of DMSO), and the mixture is agitated with avortexer until dissolution is complete.

Calibration solution 1 (20 μg/ml): 34.4 μl of the stock solution aremixed with 1000 μl of DMSO and homogenized.

Calibration solution 2 (2.5 μg/ml): 100 μl of calibration solution 1 aremixed with 700 μl of DMSO and homogenized.

Preparation of the Sample Solutions:

Sample solution for solubility up to 10 g/l in PBS buffer pH 7.4: About5 mg of the test substance are weighed accurately into a 2 ml Eppendorfsafe-lock tube (from Eppendorf, Cat. No. 0030 120.094), and PBS bufferpH 7.4 is added to a concentration of 5 g/l (e.g. 5 mg of substance+500μl of PBS buffer pH 7.4).

Sample solution for solubility up to 10 g/l in acetate buffer pH 4.6:About 5 mg of the test substance are weighed accurately into a 2 mlEppendorf safe-lock tube (from Eppendorf, Cat. No. 0030 120.094), andacetate buffer pH 4.6 is added to a concentration of 5 g/1 (e.g. 5 mg ofsubstance+500 μl of acetate buffer pH 4.6).

Sample solution for solubility up to 10 g/l in water: About 5 mg of thetest substance are weighed accurately into a 2 ml Eppendorf safe-locktube (from Eppendorf, Cat. No. 0030 120.094), and water is added to aconcentration of 5 g/l (e.g. 5 mg of substance+500 μl of water).

Procedure:

The sample solutions prepared in this way are shaken at 1400 rpm using acontrolled-temperature shaker (e.g. Eppendorf thermomixer comfort Cat.No. 5355 000.011 with exchangeable block Cat. No. 5362.000.019) at 20°C. for 24 hours. 180 μl are removed from each of the solutions andtransferred into Beckman polyallomer centrifuge tubes (Cat. No. 343621).These solutions are centrifuged at about 223 000×g for 1 hour (e.g.Beckman Optima L-90K ultracentrifuge with type 42.2 Ti rotor at 42 000rpm). 100 μl of the supernatant are removed from each sample solutionand diluted 1:5, 1:100 and 1:1000 with the solvent used in each case(water, PBS buffer 7.4 or acetate buffer pH 4.6). A portion of eachdilution is dispensed into a suitable vessel for HPLC analysis.

Analysis:

The samples are analyzed by RP-HPLC. A two-point calibration plot of thetest compound in DMSO is used for quantification. The solubility isexpressed in mg/l. Analysis sequence: 1) calibration solution 2.5 mg/ml;2) calibration solution 20 μg/ml; 3) sample solution 1:5; 4) samplesolution 1:100; 5) sample solution 1:1000.

HPLC Method for Acids:

Agilent 1100 with DAD (G1315A), quat. pump (G1311A), autosampler CTC HTSPAL, degasser (G1322A) and column thermostat (G1316A); column:Phenomenex Gemini C18, 50 mm×2 mm, 5μ; temperature: 40° C.; eluent A:water/phosphoric acid pH 2; eluent B: acetonitrile; flow rate: 0.7ml/min; gradient: 0-0.5 min 85% A, 15% B; ramp: 0.5-3 min 10% A, 90% B;3-3.5 min 10% A, 90% B; ramp: 3.5-4 min 85% A, 15% B; 4-5 min 85% A, 15%B.

HPLC Method for Bases:

Agilent 1100 with DAD (G1315A), quat. pump (G1311A), autosampler CTC HTSPAL, degasser (G1322A) and column thermostat (G1316A); column:VDSoptilab Kromasil 100 C18, 60 mm×2.1 mm, 3.5μ; temperature: 30° C.;eluent A: water+5 ml perchloric acid/1; eluent B: acetonitrile; flowrate: 0.75 ml/min; gradient: 0-0.5 min 98% A, 2% B; ramp: 0.5-4.5 min10% A, 90% B; 4.5-6 min 10% A, 90% B; ramp: 6.5-6.7 min 98% A, 2% B;6.7-7.5 min 98% A, 2% B.

C. EXEMPLARY EMBODIMENTS OF PHARMACEUTICAL COMPOSITIONS

The compounds according to the invention can be converted intopharmaceutical preparations in the following ways:

Tablet:

Composition:

100 mg of the compound according to the invention, 50 mg of lactose(monohydrate), 50 mg of maize starch (native), 10 mg ofpolyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2mg of magnesium stearate.

Tablet weight 212 mg, diameter 8 mm, radius of curvature 12 mm

Production:

A mixture of compound according to the invention, lactose and starch isgranulated with a 5% strength solution (m/m) of the PVP in water. Thegranules are dried and subsequently mixed with the magnesium stearatefor 5 minutes. This mixture is compressed in a conventional tablet press(see above for format of the tablet). A guideline compressive force forthe compression is 15 kN.

Suspension which can be Administered Orally:

Composition:

1000 mg of the compound according to the invention, 1000 mg of ethanol(96%), 400 mg of Rhodigel® (xanthan gum from FMC, Pennsylvania, USA) and99 g of water.

10 ml of oral suspension correspond to a single dose of 100 mg of thecompound according to the invention.

Production:

The Rhodigel is suspended in ethanol, and the compound according to theinvention is added to the suspension. The water is added while stirring.The mixture is stirred for about 6 h until the swelling of the Rhodigelis complete.

Solution which can be Administered Orally:

Composition:

500 mg of the compound according to the invention, 2.5 g of polysorbateand 97 g of polyethylene glycol 400. 20 g of oral solution correspond toa single dose of 100 mg of the compound according to the invention.

Production:

The compound according to the invention is suspended in the mixture ofpolyethylene glycol and polysorbate with stirring. The stirring processis continued until the compound according to the invention hascompletely dissolved.

I.V.-Solution:

The compound according to the invention is dissolved in a concentrationbelow the saturation solubility in a physiologically tolerated solvent(e.g. isotonic saline, 5% glucose solution and/or 30% PEG 400 solution).The solution is sterilized by filtration and used to fill sterile andpyrogen-free injection containers.

1. A compound of the formula (I)L-CH₂-M-Q   (I), in which L is phenyl, pyridyl, furyl, thienyl,thiazolyl, oxazolyl, isothiazolyl or isoxazolyl, each of which may besubstituted up to twice, identically or differently, by halogen, cyano,(C₁-C₄)-alkyl, trifluoromethyl and/or (C₂-C₄)-alkynyl, or is(C₅-C₇)-cycloalkyl which may be substituted up to twice, identically ordifferently, by fluorine and/or (C₁-C₄)-alkyl, M is a bicyclicheteroaryl group having one of the formulae (a) to (i)

in which * is the point of linkage to the —CH₂-L group, ** is the pointof linkage to the Q group, A, B and D are each CH, CR¹ or N, with amaximum of two of the ring members A, B and D simultaneously being N andin which R¹ is a substituent selected from the series halogen, cyano,(C₁-C₄)-alkyl, trifluoro-methyl, amino, (C₁-C₄)-alkoxy andtrifluoromethoxy, where, in the event that the substituent R¹ occursmore than once, its meanings may be identical or different, and E is Oor S, and Q is an unsaturated or aromatic 5- or 6-membered heterocyclehaving up to four heteroatoms from the series N, O and/or S, which maybe substituted up to four times, identically or differently, by radicalsselected from the group consisting of halogen, azido, nitro, cyano, oxo,thioxo, —R², —C(═O)—R², —C(═O)—OR², —C(═O)—NR²R³, —O—(C═O)_(n)—R²,—O—C(═O)—OR², —O—C(═O)—NR²R³, —S(O)_(p)—R², —SO₂—OR², —SO₂—NR²R³,—NR²—(C═O)_(n)—R³, —NR²—SO₂—R³, —NR²—C(═O)—OR³, —NR⁴—C(═O)—NR²R³ and—NR⁴—SO₂—NR²R³, in which n is the number 0 or 1, p is the number 0, 1 or2, R², R³ and R⁴ are identical or different and are independently of oneanother hydrogen, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl,(C₃-C₈)-cycloalkenyl, (C₆-C ₁₀)-aryl, 4- to 8-membered heterocyclyl or5- to 10-membered heteroaryl, and/or R² and R³ or R² and R⁴ togetherwith the radical to which they are both respectively bonded may form a4- to 8-membered heterocycle, where R², R³ and R⁴ in turn may optionallybe substituted up to five times, identically or differently, by radicalsselected from the group consisting of halogen, azido, nitro, cyano,(C₁-C₆)-alkyl, trifluoromethyl, (C₁-C₆)-acyl, hydroxycarbonyl,(C₁-C₆)-alkoxycarbonyl, aminocarbonyl, mono- anddi-(C₁-C₆)-alkylaminocarbonyl, hydroxy, (C₁-C₆)-alkoxy,trifluoromethoxy, (C₁-C₆)-acyloxy, oxo, mercapto, (C₁-C₆)-alkylthio,amino, mono- and di-(C₁-C₆)-alkylamino, (C₁-C₆)-acylamino,(C₁-C₆)-alkoxycarbonylamino, (C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkenyland 4- to 8-membered heterocyclyl, and the N-oxides, salts, solvates,salts of the N-oxides and solvates of the N-oxides and salts thereof. 2.A compound of the formula (I) as claimed in claim 1, in which L isphenyl or thienyl, each of which may be substituted up to twice,identically or differently, by fluorine, chlorine, cyano, methyl and/ortrifluoromethyl, or is cyclohexyl or cycloheptyl, each of which may besubstituted up to twice, identically or differently, by fluorine and/ormethyl, M is a bicyclic heteroaryl group of the formula (b), (d), (e) or(h)

in which * is the point of linkage to the —CH₂-L group, ** is the pointof linkage to the Q group, A, B and D are each CH, CR¹ or N, with amaximum of two of the ring members A, B and D simultaneously being N andin which R¹ is a substituent selected from the series fluorine,chlorine, bromine, cyano, (C₁-C₄)-alkyl, trifluoromethyl, amino,(C₁-C₄)-alkoxy and trifluoromethoxy, where, in the event that thesubstituent R¹ occurs more than once, its meanings may be identical ordifferent, and E is O or S, and Q is a group of the formula

in which # is the point of linkage to the M group, G is CH or N, J isCR⁷ or N, Z is O or S, R⁵, R⁶ and R⁷ are identical or different and areindependently of one another a radical selected from the groupconsisting of halogen, nitro, cyano, —R², —C(═O)—R², —C(═O)—OR²,—C(═O)—NR²R³, —O—(C═O)_(n)—R², —O—C(═O)—OR², —O—C(═O)—NR²R³,—S(O)_(p)—R², —SO₂—OR², —SO₂—NR²R³, —NR²—(C═O)_(n)—R³, —NR²—SO₂—R³,—NR²—C(═O)—OR³, —NR⁴—C(═O)—NR²R³ and —NR⁴—SO₂—NR²R³, in which n is thenumber 0 or 1, p is the number 0 or 2, R², R³ and R⁴ are identical ordifferent and are independently of one another hydrogen, (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkenyl, phenyl, 5- to7-membered heterocyclyl or 5- or 6-membered heteroaryl, and/or R² and R³or R² and R⁴ together with the radical to which they are bothrespectively bonded may form a 5- to 7-membered heterocycle, where R²,R³ and R⁴ in turn may optionally be substituted up to three times,identically or differently, by radicals selected from the groupconsisting of fluorine, chlorine, cyano, (C₁-C₄)-alkyl, trifluoromethyl,hydroxy, (C₁-C₄)-alkoxy, trifluoromethoxy, oxo, amino,mono-(C₁-C₄)-alkylamino and di-(C₁-C₄)-alkylamino, R⁸ is hydrogen,(C₁-C₆)-alkyl or (C₃-C₇)-cycloalkyl, where (C₁-C₆)-alkyl may besubstituted up to five times by fluorine and up to twice, identically ordifferently, by (C₃-C₇)-cycloalkyl, hydroxy, (C₁-C₄)-alkoxy,trifluoromethoxy, (C₁-C₄)-acyloxy, amino, mono-(C₁-C₄)-alkylamino,di-(C₁-C₄)-alkylamino, (C₁-C₄)-acylamino, hydroxycarbonyl,(C₁-C₄)-alkoxycarbonyl, aminocarbonyl, mono-(C₁-C₄)-aminocarbonyl,di-(C₁-C₄)-alkylaminocarbonyl and/or a 5- or 6-membered heterocycle, R⁹is (C₁-C₄)-alkyl which may be substituted by hydroxy, (C₁-C₄)-alkoxy,amino, mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino or up to threetimes by fluorine, R¹⁰ has the meaning indicated above for R⁸, and R¹¹is hydrogen or (C₁-C₄)-alkyl, and the N-oxides, salts, solvates, saltsof the N-oxides and solvates of the N-oxides and salts thereof.
 3. Acompound of the formula (I) as claimed in claim 1, in which L is phenylwhich may be substituted up to twice by fluorine, M is a bicyclicheteroaryl group of the formula (a-3), (b-3) or (c-3)

in which * is the point of linkage to the —CH₂-L group and ** is thepoint of linkage to the Q group, and Q is a group of the formula

in which # is the point of linkage to the M group, J is CR⁷ or N, R⁵ andR⁶ are independently of one another hydrogen or amino, R⁷ is hydrogen,fluorine, chlorine, bromine, (C₁-C₄)-alkyl, (C₃-C₆)-cycloalkyl, pyridylor —NR¹²R¹³, in which R¹² is hydrogen or (C₁-C₄)-alkyl which may besubstituted by hydroxy, methoxy or up to three times by fluorine, R¹³ ishydrogen, (C₁-C₄)-alkyl which may be substituted by hydroxy, methoxy orup to three times by fluorine, or (C₁-C₄)-acyl, (C₁-C₄)-alkoxycarbonylor mono- or di-(C₁-C₄)-alkylaminocarbonyl, or R¹² and R¹³ together withthe nitrogen atom to which they are bonded form a 5- to 7-memberedheterocycle which may be substituted by oxo, and R⁸ is hydrogen or(C₁-C₄)-alkyl which may be substituted up to three times by fluorine,and the N-oxides, salts, solvates, salts of the N-oxides and solvates ofthe N-oxides and salts thereof.
 4. A compound of the formula (I) asdefined in claim 1 for the treatment and/or prophylaxis of diseases. 5.(canceled)
 6. A pharmaceutical composition comprising a compound of theformula (I) as defined in claim 1 in combination with an inert,non-toxic, pharmaceutically suitable excipient.
 7. The pharmaceuticalcomposition of claim 6 further comprising an active ingredient selectedfrom the group consisting of organic nitrates, NO donors, cGMP-PDEinhibitors, agents having antithrombotic activity, agents lowering bloodpressure, and agents altering lipid metabolism.
 8. The pharmaceuticalcomposition as claimed in claim 6 for the treatment and/or prevention ofheart failure, angina pectoris, hypertension, pulmonary hypertension,ischemias, vascular disorders, thromboembolic disorders andarteriosclerosis.
 9. A method for the treatment and/or prevention ofheart failure, angina pectoris, hypertension, pulmonary hypertension,ischemias, vascular disorders, thromboembolic disorders andarteriosclerosis in humans and animals by administering an effectiveamount of at least one compound of the formula (I) as defined inclaim
 1. 10. A method for the treatment and/or prevention of heartfailure, angina pectoris, hypertension, pulmonary hypertension,ischemias, vascular disorders, thromboembolic disorders andarteriosclerosis in humans and animals by administering an effectiveamount of the pharmaceutical composition of claim 6.